Enhancer of zeste homolog2 (EZH2) is a SET-domain-containing histone lysine N-methyltransferase that participates in the epigenetic regulation of cell lineage determination and homeostasis. EZH2 forms the Polycomb repressive complex2 (PRC2) with embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12) to catalyze histone H3 Lys27 trimethylation, and hyperactivity of this enzymatic function has been linked to aberrant repression of tumor suppressor genes in diverse cancers.
Epigenetic modifications of DNA and histones by a variety of protein complexes produce combinatorial codes of chromatin modification, amplifying the complexity of how genetically encoded information is employed. Such epigenetic information is decoded by “reader” proteins that, in conjunction with transcription factors, regulate the differential expression of genes during development and homeostasis. Two broad classes of protein complexes, Trithorax (trxG) and Polycomb (PcG), are responsible for the deposition of histone marks that dictate whether a gene is activated or repressed, respectively1-5. TrxG generally maintains an ‘on state’ of gene expression by catalyzing methylation of Lys4 of Histone H3 (H3K4), while PcG maintains an ‘off state’ by catalyzing trimethylation of Lys27 of Histone H3 (H3K27). In mammals, there are two distinct PcG complexes, Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2). PRC2 catalyzes trimethylation of H3K27 and, at certain sites, facilitates the recruitment of PRC1 to methylated histones to repress target genes3,4. PRC2 is composed of three essential core components, enhancer of zeste homolog 2 (EZH2), suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The conserved suppressor of variegation, enhancer of zeste, trithorax (SET) domain of EZH2 represents the active site for catalysis of H3K27 methylation6.
In addition to the established roles of the epigenetic machinery in cell homeostasis and development, recent studies have implicated discrete protein subcomponents, such as EZH2, in the pathogenesis of diverse cancers7-12. EZH2 overexpression has been linked to repression of tumor suppressor genes and derepression of genes involved in metastasis13-16. In certain cancers, this EZH2 deregulation has been linked to pathologic alterations in microRNA levels17-20. Somatic mutations that alter the substrate specificity and functional activity of EZH2 have also been found in B cell non-Hodgkin's lymphoma21-24. Correspondingly, reduced expression of EZH2 by shRNA or siRNA induces proliferative arrest in cancer cell lines that overexpress EZH225,26. The genetic ablation of Ezh2 alone prevents the development of a murine T cell lymphoma that results from inactivation of Snf5, a core component of the Swi/Snf remodeling complex27. Collectively, these findings implicate EZH2 deregulation in the development and maintenance of cancer.